Unitedo States ' Patent‘ [191 [111 4,215,691 .Wong. I [45] Aug. 5, 1980

[54] BLOCK COPOLSJMER OTHER PUBLICATIONS - v ‘ _ Encyclopedia of Polymer Science & Technology, vol. 15, [75] Inventor: Patrick S. Wong, P1110 Alto, Callf- pp. 508-530, 1971, Interscience Publishers, Inc. 73 A - : A!” Pa] Alto, Cab-L Primary Examiner-Robert W. Michell [ 1 sslgnec W0.’ 0 Assistant Examiner—C. F. Rosenbaum [21] App], No; 950,454 Attorney. Agent, or Finn-Paul L. Sabatine; Edward L. _ Mandell; Thomas E. Ciotti

An intravaginal contraceptive system for the pre-pro RM U'S' M M grammed, unattended delivery of an antifertility steroid [62] Division of Ser. No. 775,718, Mar. 9, 1911, abandoned. is disclosed- The system comprises (a) an antifertility steroid, (b) a delivery module comprising a reservoir for [51] Int. Cl.2 ...... A61F 5/46 storing the steroid in an amount for execution of the [52] US. Cl...... 128/260 program, a rate controller which maintains the rate of [58] Field of Search ...... 128/213, 223, 251, 260, steroid delivered in a contraceptive effective amount 128/261, 268, 270-271; 424/19, 31 throughout the life of the system, an energy source for _ transferring steroid from the reservoir to the vagina, [56] References Cited and a portal for releasing the steroid from the module to Us. PATENT DOCUMENTS the vagina, (c) a platform which integrates the module 3 545 439 12/1970 Dun 128/260 into a unit sized, shaped and adapted for insertion and 1 ' “n _' ------" retention in a vagina, and (d) a contraceptive program g’ggg’ggg imam“ ' ‘ ' ' ‘ ' ' ' ‘ ‘ " which provides for the controlled release of steroid to 3,967,618 1/1916 '.'.'.'.'.'..... I: 128/260 Pr°d“°° ‘"1 amifm?ity effect We‘ ‘‘ Pmlmlged Peri“! 3,991,760 11/1916 Drobish er al...... 128/260 “11m 3,993,073 11/ 1976 Zaffaroni ...... 128/260 4,012,496 3/1911 Schiip?in et n...... 128/260 7 Claims, 3 Drawing Figures U.S. Patent ' Aug. 5, 1980 4,215,691

FIG.| 4,215,691 1 2 progestational and estrogenic steroids at a controlled VAGINAL CONTRACEPTIVE SYSTEM MADE and useful rate over prolonged periods of time. FROM BLOCK COPOLYMER Another object of the invention is to provide an intra vaginal delivery system manufactured with vaginally CROSS-REFERENCE TO COPENDING 5 compatible materials for releasing antifertility steroids vAPPLICATION over a prolonged period of time. 4 This patent application is a division of U.S. patent Other objects, features, aspects and advantages of the application Ser. No. 775,718 ?led on Mar. 9, 1977 and invention will be more apparentto those versed in the now abandoned. This application and application Ser. art from the following detailed speci?cation, taken in No. 775,718 both are assigned to the ALZA Corpora conjunction with the accompanying claims. tion of Palo Alto, Calif. SUMMARY OF THE INVENTION FIELD OF THE INVENTION This invention concerns an intravaginal system useful This invention pertains to an intravaginal system. The for delivering antifertility steroids. The system com system comprises an antifertility steroid, a delivery prises a wall made of a block copolymer of styrene and module, a platform and a contraceptive program that butadiene surrounding a reservoir containing an inner operates as a unit for delivering an effective amount of liquid mass transfer conductor and an antifertility ste an antifertility steroid to the vagina of a fertile female. roid. .T he wall and the carrier are permeable to the More speci?cally, the invention relates to an intrava passage of steroid by diffusion, but the permeability of ginal contraceptive system manufactured from block the wall to the passage of steroid is lower than through copolymers of styrene and butadiene in the form of an the carrier. Since the permeability through the wall is intravaginal device for delivering an antifertility ste lower, passage through the wall is the rate determining roid. step for releasing an effective amount of steroid from the operable system to the vagina. BACKGROUND OF THE INVENTION 25 Vaginal devices for delivering a drug are known to BRIEF DESCRIPTION OF THE DRAWINGS the prior art. For example, U.S. Pat. No. 3,545,439 In the drawings, which are not drawn to scale, but are issued to Gordon W. Ducan discloses an intravaginal set forth to illustrate various embodiments of the inven ring-shaped device that can be made of varying types of tion, the ?gures are as follows: polymeric materials. The device is formed of a solid 30 FIG. 1 illustrates an intravaginal system sized, shaped polymer containing drug that is released by diffusion to and adapted for insertion and retention in a vagina; the vagina. The device optionally contains a tension FIG. 2 illustrates the intravaginal system of FIG. 1 as spring for keeping it in the vagina. In U.S. Pat. No. seen in a cross-section, opened‘ view and manufactured 3,920,805 patentee Theodore J. Roseman discloses a 35 with an internal reservoir; and, solid, polymeric device that has a nonmedical central FIG. 3 illustrates the intravaginal system of FIG. 1 in core and an encircling medicated coating of the poly opened section showing means, for ?lling the system. mer. The device releases drug by diffusion and in a In the drawings and speci?cation, like parts in related preferred embodiment, the device is ring-shaped with a ?gures are identi?ed by numbers. The terms appearing [?at tensioning spring molded in the nonmedicated cen earlier in the speci?cation and in the description of the tral core. 40 While, the above-described devices are useful for drawings, as well as embodiments thereof, are further certain applications, serious disadvantages are fre- ‘ described elsewhere in the disclosure. quently associated with these devices that limit their DETAILED DESCRIPTION OF THE use. For example, generally the polymers used by the DRAWINGS prior art are thermoset polymers which require molding 45 and curing fabrication procedures to form solid devices. Turning now to the drawings in detail, which are These fabrication procedures tend to restrict the shape examples of intravaginal contraceptives that can be of the device, and the use of said polymers limits the used for releasing an antifertility hormone to the vagina amount of drug that can be loaded into the polymer and for the management of contraception, and which exam leads to a more rigid device. Those versed in the art will 50 ples are not‘to be construed as limiting the invention, recognize that if vaginal devices can be provided made one embodiment thereof is seen in FIG. 1 and identi?ed of materials that are essentially free from the above by the numeral 10. The phrase “intravaginal contracep tribulations, such devices would be a valuable advance tive system” as used herein refers to a controlled dosage ment in the art and a useful improvement. form which provides pre-programmed, unattended de 55 livery of hormone, and for a time period, established to OBJECTS OF THE INVENTION meet a speci?c contraceptive need. Accordingly, it is an immediate object of this inven System 10, as seen in FIG. 2, comprises an antifertil tion to provide an improved intravaginal delivery sys ity steroid 11, selected for producing a desired contra tem for the controlled and continuous delivery of anti ceptive effect when delivered to the target receptor site, fertility steroid over a prolonged period of time. the vagina, and a delivery module 12. Delivery module Yet another object of the invention is to provide'an 12 is essentially the body of system 10 and it comprises intravaginal system comprising materials easy to fabri (a) a reservoir 13 for storing an amount of hormone 11 cate into systems and which materials can release anti required for execution of the prescribed contraceptive fertility steroids at meaningful rates over a prolonged program, (b) a rate controller 14, or wall formed of a period of time. styrene-butadiene copolymer that maintains the pre Yet still another object of the invention is to provide scribed rate of steroid administered throughout the life an intravaginal delivery system that is ?exible, can have of system 10, (c) an energy source 11, or the concentra high steroid loading, and which system can deliver tion of steroid 11 in reservoir 13 that provides the driv 4,215,691 3 4 ing means for transferring steroid 11 from a higher amount in reservoir 13 to rate controller 14, (d) an inner CH; CH CH; CH=CHCH2 y CH; CH mass transfer conductor 15 for housing steroid 11 in reservoir 13, and (e) a portal 14 which in this invention is rate controller 14 that provides the exit from module 12 to the vagina. _ System 10, comprising steroid 11 stored in module 12 X which module 12, is integrated into a unit sized, shaped and adapted as a platform for placing in the vagina can wherein x is 5X 101 to 10X l04and y is 1X 103 to 2x104. embrace many shapes. That is, the platform can have Generally, in a more preferred range the styrene block copolymer will have a molecular weight in the range of various continuous, curved shapes, such as annular, or 10,000 to 20,000 and the butadiene will have a molecu ring, oval, ellipse, toroidal, and the like. The novel lar weight in the range of 40,000 to 100,000. The styrene antifertility system 10 can be used for delivering steroid butadiene block copolymers suitable for the present 11 to animals, warm-blood mammals including humans purpose are permeable to antifertility effective amounts and primates, farm animals and laboratory animals. The of progestational and estrogenic vaginally administrable dimensions of the system will vary depending on the steroids by diffusion, and these copolymers are known to the art and they can be synthesized according to the host and the shape used for delivering the steroid. For 20 procedures disclosed in Encyclopedia of Polymer Science example, at its maximum dimension the device will and Technology, Vol. 15, pages 508 to 530, 1971, pub measure from one loci on the wall to a distant loci on lished by Interscience Publishers, Inc., New York; Poly the wall of from 0.4 cm to 12 cm, with presently pre mers, Vol 17, 938 to 956, 1976; Technical Bulletin SCR ferred devices exemplified by an annular shaped system 159, 1965, Shell Corp., New York; and references cited which can have an external diameter of from 0.5 cm to therein. 16 cm, with general dimensions for various hosts as Exemplary inner mass transfer conductor 15 that are follows: humans 6 cm to 12 cm, sheep 2 cm to 7 cm, carriers suitable for housing steroid 11 in reservoir 13 are those liquid carriers permeable to the passage of dogs 0.5 cm to 5.0 cm, swine 2 cm to 7.5 cm, household both progestational and estrogenic steroids. These car cats 0.4 cm to 4 cm and dairy cattle 5 cm to 12 cm. riers include liquids capable of containing dissolved and DETAILED DESCRIPTION OF THE undissolved steroid 11, and also capable of forming a liquid carrier wall interface at the inner surface of sty INVENTION rene butadiene wall 14. Typical carriers include a mem In accordance with the practice of this invention, it 35 ber selected from the group consisting of alkylene gly has now been unexpectedly found that certain vaginally cols, dialkylene glycols, poly(alkylene glycols), vegeta acceptable block copolymers of styrene and butadiene ble oils, animal oils, fruit oils, nut oils, marine oils, syl van oils, inorganic oils, aqueous media such as water can be used for forming rate controller 14 of intrava ‘mixed with poly(alkylene glycols) including poly(ethy ginal system 10 for the controlled release of steroid 11 lene glycols) having a molecular weight of 400 to 6000, by diffusion. The use of these materials is unexpected poly(propylene glycol) having a molecular weight of because the copolymer can be successfully used sub 500 to 2000, glycerol polysorbate 80 and the like. Exam stantially free of any adverse affect on the vagina. The ples of carriers are known to the art in Pharmaceutical vagina is lined with an extremely delicate tissue and it is Sciences. by Remington, 1970, published by Mack Pub essential, therefore, that materials forming system 10 do 45 lishing Company, Easton Pa. not adversely affect the vagina. The copolymers used In the specification and the accompanying claims, the phrase “anti-fertility steroid” and the term “steroid” are for the purpose of this invention are the vaginally com used interchangeably and they broadly include proges patible materials set forth below. By compatible is tational substances that have antifertility properties and meant the materials are pharmaceutically acceptable estrogenic substances that have anti-fertility properties. within the environment of the vagina and generically to These substances can be of naturally occurring or syn the host. That is, these materials do not break down in thetic origin and they generally possess a cyclopentano the vagina, there is no absorption of the materials and phenanthrene nucleus. The term progestational sub there is no deleterious action on the sensitive tissues in stance as used herein embraces “progestogen” which term is used in the pharmaceutically acceptable steroid the area of the placement and retention of system 10 art to generically describe steroids possessing progesta over a prolonged period of time. tional activity, and the former also includes “proges The styrene-butadiene block copolymer useful for tins,” a term widely used for synthetic steroids that have manufacturing rate controller 14 includes those gener progestational effects. The active anti-fertility progesta ‘ ally formed by initiation at a chain end of an already 60 tional agents that can be used to produce the desired formedpolymeric chain. The block copolymers are effects in mammals, including humans, and primates, thermoplastic elastomers because of their ability to be include without limitations: pregn-4-ene-3,20-dione, also known as progesterone; l9-nor-pregn-4-3n3-3,20 come ?uid and moldable at elevated temperatures. dione; l7-hydroxy-l9-nor-l7a-pregn-5(l0)-ene~20-yn These properties lend themselves to the manufacture of 65 3-one; dl-l 1a-ethyl-l7-ethinyl-17-a-hydroxygon-4-ene system 10. The block copolymer useful for the present 3-one; 17-ethynyl-l7-hydroxy-5(l0)-estren'3-one; 17a purpose can be represented by the following general ethynyl-l9-norestosterone;6-chloro-l7-hydroxypregna formula: 4,6-diene-3,20-dione; l7a-hydroxy-6ct-methyl-l7(-l ' ‘4,215,691 ‘glycol having a molecular weight ‘of 600; and a system of toroidal shape-with a wallrthicknesszof 2.79:0.08 mm containing in the reservoir 50% progesterone and 50% polyethylene glycol having a molecular weight of ' ghydroxy-6a-methylpregn#4-ene-3,20rdione;. mixtures 600. The other dimensions were as“ previously de

thereof and the like; ‘ i ' ' ‘ scribed. ' ' - The terms estrogenic and estrogenic anti-fertility The delivery of ‘steroids at meaningful rates‘ from agents as-used herein‘ alsoincludes the compounds three systems made according to the mode of the inven known as estrogens that possess anti-fertility‘properties tion was measured from three toroidal shaped systems. ‘including a-estradioL. a-e's'tradiol i-benzoate,v 'l7-d The results werefas follows: (1) a system having a wall , cyclopentanepropionate estradiol, l-,3',5(l0)-estr'atriene thickness of 2.79i-0.08 mm and a progesterone loading 3,17a-diol dipropionate, estra-l,3,5(l0)-triene 3,17-d ' of 0.7 gr had a steady state of release rate of 5.63:0.24 diol valerate, estrone, ethynyl estradiol, l7-ethynyl mg per day; (2) a system having a wall thickness of estradiol-3-methyl ether, l7-ethinyl estradiol-34cyclo l.78i0‘.08-mm‘and va progesterone loading of 1.3 gr had pentoether, estriol, mixtures thereof‘, and the like. Gen 'a's'teady state release'r'ate of 9.49:0.25 mg per day; and , e'rally, reservoir 13.will contain from 25 nanograms to 5 grams of progestational or estrogenic steroidfor release (3) 'ai'system having ‘:i' wall ‘ thickness of 0.75 $0.08 ‘mm at the rate of 0.05 micrograms to--50 milligrams per, day, and-aenorethindrone loading 3of 0.4 gr ‘had a steady state and in a presently preferred range of 0.5 milligrams; to release rate of ‘0.56:0.07 mg per day as measured over v‘it prolongedperiod of 120 days. =' - 6.0 milligrams per day to the uterus of an adult child .20 I bearing woman. Generally, the system can be used from systems-containing norethisterone were placed a period of 1 day to 1 year, or longer. in the vagina of fertile women. The systems were com Additionally, the above progestational and estrogenic fortable and well-received by the vagina and the host. agents can be in the form of their pharmacologically The systems are preferably placed between the rear accepted derivatives, such as their hydroxy or keto 25 endometrial wall of the vagina and the upper edge of groups can be in a derivative form for the present pur the pubic bone. In this place, the medicating system pose. The progestational or estrogenic derivative used releases a contraceptively effective amount of steroid should easily convert to the parent agent upon its re over a prolonged period of 75 days to yield the intended lease from the device by biological activities such as effect. enzymatic transformation, pH assisted hydrolysis in 30 It will be understood to those versed in the art in the uteri, tissue and metabolism and the like. The derivative light of the present speci?cation, drawings and the ac can also be used to control the solubility of the agent in companying claims that the invention makes available the liquid core and to assist in metering the agent from to the art both a novel and useful intrauterine ‘system for the device. Suitable derivatives include without limita delivering progestational and estrogenic steroids to tion, esters with pharmaceutically acceptable acids such 35 produce a desired antifertility effect; and, the rate of as acetate, glucuronate, benzoate, propionate, butyrate, release from these systems can be controlled to produce valeroate, hexanoate, heptanoate, maleate, citrate, suc this effect, while simultaneously overcoming the prob cinate, tartrate,'fumarate, malate, ascorbate, sulphate, lems associated with the prior art. It will be further phosphate and the like; ethers such as lower alkoxy-tet understood to those versed in the art that different em rahydropyran-yl, unsubstituted tetrahydropyranyl, silyl 40 bodiments of this invention can be made without de moieties, trifluoromethyloxy, cyclopentyl enol ethers ‘parting from the spirit and the scope of the invention. and other functional groups such as ureido, and the like. ' Accordingly, it is to be understood the invention is not The intravaginal systems used for the purpose of this to be construed as limited, but it embraces all equiva invention are manufactured as follows: First, a section lents inherent herein. of the above-described styrene butadiene block copoly 45 We claim: mer vaginal acceptable tubing was washed with water 1. An improved vaginal contraceptive system for for 48 to 56 hours, and then dried in air at room temper delivering an antifertility steroid, comprising: ature. Then, the tubing was cut into appropriate lengths (a) a body sized, shaped and adapted for easy inser and shaped like a ring, as seen in FIG. 3, and molded tion and comfortable retention in the vagina, said into a torus at 165' C. Next, a solid polymeric plug 17, 1 50 'body comprising; having an outside diameter equivalent to the inside (b) a shaped wall surrounding and forming a reser diameter of the tube was very lightly dampened with methylene chloride and inserted into the tube for join voir; ing the opened tube at its two ends, thereby forming a (c) an antifertility steroid selected from the group closed system. Then the hollow ring is ?lled by inject: 55 consisting of progestational and estrogenic steroids ing a steroid carrier mixture into reservoir 13 through in the reservoir; ‘ inlet port or needle 18 with continuous filling of reser (d) a liquid carrier permeable to the passage of steroid voir 13 until all the air is displaced through outlet port and containing an amount of steroid for prolonged or needle 19. This procedure completely ?lls reservoir release in the reservoir; 13. Finally, the needle punctures were sealed with a 60 (e) the improvement comprising forming the wall of little methylene chloride. Reservoir 13 was filled with non-toxic, vaginally acceptable release rate con progesterone in polyethylene glycol having a molecular trolling thermoplastic styrene butadiene block 00-‘ weight of 400, 50% wt/wt. polymer permeable to the passage of steroid; and, Additional systems 10 were prepared having a toroi (f) wherein the system when in operation and placed dal shape of the same copolymer with a wall 14 having 65 in the vagina releases at a controlled rate a con a thickness of 1.78:0.08 mm, an internal diameter of 6 traceptively effective amount of steroid over a mm, an outside diameter of 4.4 cms, and a reservoir prolonged period of time to produce the desired containint 35% progesterone and 65% polyethylene antifertility effect. 4,215,691 2. The improved vaginal system for delivering steroid a member selected from the group consisting of proges according to claim 1, wherein the block copolymer has terone, l7a-hydroxyprogesterone, nor‘ethindrone, nore the following formula: ‘ thisterone acetate, norgestrel, norethynodrel, and me thoxyprogesterone. 5. The improved vaginal system for delivering a ste CH2 CH CH1 CH=CHCH2 CH2 CH‘ roid according to claim 1, wherein the estrogenic ste roid is a member selected from the group consisting of estradiol, estrone, ethynyl estradiol, es'trio‘l, l7-ethynyl estradiol-B-methyl ether, and a-estradiol 3-benzoate. 6. The improved vaginal system for delivering a ste x x roid according to claim 1, wherein the system is ring shaped. wherein x is 5X 101 to 10X 104 and y is 1X 103 to 2X10‘. 7. The improved vaginal system for delivering a ste 3. The improved vaginal system for delivering steroid roid according to claim 1, wherein the system is toroi according to claim 1, wherein the carrier is a member selected from the group consisting of alkylene glycols, dal-shaped, the steroid is selected from the group con dialkylene glycols, poly(alkylene glycols), and aqueous sisting of progesterone and norethindrone, and the car media mixed with poly(alkylene glycols). rier is polyethylene glycol having a molecular weight of 4. The improved vaginal system for delivering steroid 400 to 6000. according to claim 1, wherein the progestional steroid is i t l i #

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